Tip60 is a haplo-insufficient tumour suppressor required for an oncogene-induced DNA damage response

Abstract

The acetyl-transferase Tip60 might influence tumorigenesis in multiple ways. First, Tip60 is a co-regulator of transcription factors that either promote or suppress tumorigenesis, such as Myc and p53. Second, Tip60 modulates DNA-damage response (DDR) signalling, and a DDR triggered by oncogenes can counteract tumour progression. Using E(mu)-myc transgenic mice that are heterozygous for a Tip60 gene (Htatip) knockout allele (hereafter denoted as Tip60+/- mice), we show that Tip60 counteracts Myc-induced lymphomagenesis in a haplo-insufficient manner and in a time window that is restricted to a pre- or early-tumoral stage. Tip60 heterozygosity severely impaired the Myc-induced DDR but caused no general DDR defect in B cells. Myc- and p53-dependent transcription were not affected, and neither were Myc-induced proliferation, activation of the ARF-p53 tumour suppressor pathway or the resulting apoptotic response. We found that the human TIP60 gene (HTATIP) is a frequent target for mono-allelic loss in human lymphomas and head-and-neck and mammary carcinomas, with concomitant reduction in mRNA levels. Immunohistochemical analysis also demonstrated loss of nuclear TIP60 staining in mammary carcinomas. These events correlated with disease grade and frequently concurred with mutation of p53. Thus, in both mouse and human, Tip60 has a haplo-insufficient tumour suppressor activity that is independent from-but not contradictory with-its role within the ARF-p53 pathway. We suggest that this is because critical levels of Tip60 are required for mounting an oncogene-induced DDR in incipient tumour cells, the failure of which might synergize with p53 mutation towards tumour progression.

The p400/Tip60 ratio is critical for colorectal cancer cell proliferation through DNA damage response pathways

“…By real-time PCR analysis, we found that Tip60 mRNA is underexpressed in 72 out of 74 cancers (T) compared to adjacent normal (N) tissue (Figure 1a; see Supplementary data 2 for all T/N ratios). This decrease is highly significant (Po0.000001, one-sided binomial exact test) and was expected because similar results were already reported (Lleonart et al, 2006;Gorrini et al, 2007). Importantly, sequencing of the entire Tip60 cDNA in four tumoral samples shows that Tip60, although underexpressed, is not mutated in tumors.…”

“…Taken together, these data suggest that a decrease of Tip60 function is likely to be causal for colon cancer progression by preventing apoptosis. In agreement with this possibility, a twofold decrease of Tip60, which is within the range of what we observe in colorectal cancer, favors tumorigenesis in a mouse model of lymphoma (Gorrini et al, 2007). This haploinsufficient tumor suppressor effect has been attributed to a function of Tip60 in the DDR pathway induced by oncogenic stress, which is a known anticancer pathway in mammals.…”

“…A twofold decrease in Tip60 function can be detrimental to the DNA damage response (DDR) pathway induced by oncogenic stress (Gorrini et al, 2007). We thus investigated the efficiency of this pathway in HCT116 cells.…”

“…The Tip60 histone acetyltransferase has been recently shown to be underexpressed in many human cancers from various origins (Lleonart et al, 2006;Gorrini et al, 2007). Moreover, in a model of tumor induction in mice, it has been shown to function as a haploinsufficient tumor suppressor, providing a causal link between Tip60 underexpression and tumorigenesis (Gorrini et al, 2007).…”

“…Moreover, in a model of tumor induction in mice, it has been shown to function as a haploinsufficient tumor suppressor, providing a causal link between Tip60 underexpression and tumorigenesis (Gorrini et al, 2007).…”